World Journal of Microbiology and Biotechnology

, Volume 30, Issue 9, pp 2337–2342 | Cite as

Laboratory testing of clinically approved drugs against Balamuthia mandrillaris

  • Huma Kalsoom
  • Abdul Mannan Baig
  • Naveed Ahmed Khan
  • Ruqaiyyah Siddiqui
Original Paper

Abstract

Balamuthia mandrillaris is a free-living protist pathogen that can cause life-threatening granulomatous amoebic encephalitis. Given the lack of effective available drugs against B. mandrillaris encephalitis with a mortality rate of more than 90 %, here we screened drugs, targeting vital cellular receptors and biochemical pathways, that are already in approved clinical use for their potential clinical usefulness. Amoebicidal assays were performed by incubating B. mandrillaris with drugs (3 × 105 cells/0.5 mL/well) in phosphate buffered saline for 24 h and viability was determined using Trypan blue exclusion staining. For controls, amoebae were incubated with the solvent alone. To determine whether effects are reversible, B. mandrillaris were pre-exposed to drugs for 24 h, washed twice, and incubated with human brain microvascular endothelial cells, which constitute the blood–brain barrier as food source, for up to 48 h. Of the ten drugs tested, amlodipine, apomorphine, demethoxycurcumin, haloperidol, loperamide, prochlorperazine, procyclidine, and resveratrol showed potent amoebicidal effects, while amiodarone and digoxin exhibited minimal effectiveness. When pre-treated with these drugs, no viable trophozoites re-emerged, suggesting that drugs destroyed parasite irreversibly. Based on the in vitro assay, amlodipine, apomorphine, demethoxycurcumin, haloperidol, loperamide, prochlorperazine, procyclidine, and resveratrol are potential antimicrobials for further testing against B. mandrillaris encephalitis. These findings may provide novel strategies for therapy but further research is needed to determine clinical usefulness of aforementioned drugs against granulomatous amoebic encephalitis caused by B. mandrillaris, and other free-living amoebae, such as Acanthamoeba spp., and Naegleria fowleri.

Keywords

Balamuthia mandrillaris Clinical drugs In vitro Amoebicidal Encephalitis 

References

  1. Alsam S, Kim KS, Stins M, Rivas AO, Sissons J, Khan NA (2003) Acanthamoeba interactions with human brain microvascular endothelial cells. Microb Pathog 35:235–241CrossRefGoogle Scholar
  2. Aqeel Y, Iqbal J, Siddiqui R, Gilani AH, Khan NA (2012) Anti-Acanthamoebic properties of resveratrol and demethoxycurcumin. Exp Parasitol 132:519–523CrossRefGoogle Scholar
  3. Baig AB, Iqbal J, Khan NA (2013) In vitro efficacy of clinically available drugs against growth and viability of Acanthamoeba castellanii keratitis isolate belonging to the T4 genotype. Antimicrob Agents Chemother 57:3561–3567CrossRefGoogle Scholar
  4. Booton GC, Carmichael JR, Visvesvara GS, Byers TJ, Fuerst PA (2003) Genotyping of Balamuthia mandrillaris based on nuclear 18S and mitochondrial 16S rRNA genes. Am J Trop Med Hyg 68:65–69Google Scholar
  5. Brunton LL, Chabner BA, Knollman BC (2011) Goodman and Gilman’s the pharmacological basis of therapeutics, 12th edn. McGraw-Hill, New YorkGoogle Scholar
  6. Daly JW, Harper J (2000) Loperamide: novel effects on capacitative calcium influx. Cell Mol Life Sci 57:149–157CrossRefGoogle Scholar
  7. Denney CF, Iragui VJ, Uber-Zak LD, Karpinski NC, Ziegler EJ, Visvesvara GS, Reed SL (1997) Amebic meningoencephalitis caused by Balamuthia mandrillaris: case report and review. Clin Infect Dis 25:1354–1358CrossRefGoogle Scholar
  8. Diaz JH (2011) The public health threat from Balamuthia mandrillaris in the southern United States. J La State Med Soc 163:197–204Google Scholar
  9. Dudley R, Alsam S, Khan NA (2007) Cellulose biosynthesis pathway is a potential target in the improved treatment of Acanthamoeba keratitis. Appl Microbiol Biotechnol 75:133–140CrossRefGoogle Scholar
  10. Eichhorn EJ, Gheorghiade M (2002) Digoxin. Prog Cardiovasc Dis 44:251–256CrossRefGoogle Scholar
  11. Hanauer SB (2008) The role of loperamide in gastrointestinal disorders. Rev Gastroenterol Disord 8:15–20Google Scholar
  12. Jevtovic-Todorovic V, Meyenburg AP, Olney JW, Wozniak DF (2003) Anti-parkinsonian agents procyclidine and ethopropazine alleviate thermal hyperalgesia in neuropathic rats. Neuropharmacology 44:739–748CrossRefGoogle Scholar
  13. Matin A, Siddiqui R, Jayasekera S, Khan NA (2008) Increasing importance of Balamuthia mandrillaris. Clin Microbiol Rev 21:435–438CrossRefGoogle Scholar
  14. Mattana A, Biancu G, Alberti L, Accardo A, Delogu G, Fiori PL, Cappuccinelli P (2004) In vitro evaluation of the effectiveness of the macrolide rokitamycin and chlorpromazine against Acanthamoeba castellanii. Antimicrob Agents Chemother 48:4520–4527CrossRefGoogle Scholar
  15. Millan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (2002) Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes. J Pharmacol Exp Ther 303:791–794CrossRefGoogle Scholar
  16. Schuster FL, Visvesvara GS (2004) Free-living amoebae as opportunistic and non-opportunistic pathogens of humans and animals. Int J Parasitol 34:1001–1007CrossRefGoogle Scholar
  17. Siddiqui R, Matin A, Warhurst D, Stins M, Khan NA (2007) Effect of antimicrobial compounds on Balamuthia mandrillaris encystment and human brain microvascular endothelial cell cytotoxicity. Antimicrob Agents Chemother 51:4471–4473CrossRefGoogle Scholar
  18. Siddiqui R, Jarroll EL, Khan NA (2009) Balamuthia mandrillaris: staining properties of cysts and trophozoites and the effect of 2,6-dichlorobenzonitrile and calcofluor white on encystment. J Eukaryot Microbiol 56:136–141CrossRefGoogle Scholar
  19. Siddiqui R, Aqeel Y, Khan NA (2013) Killing the dead: chemotherapeutic strategies against free-living cyst-forming protists (Acanthamoeba sp. and Balamuthia mandrillaris). J Eukaryot Microbiol 60:291–297CrossRefGoogle Scholar
  20. Stins MF, Gilles F, Kim KS (1997) Selective expression of adhesion molecules on human brain microvascular endothelial cells. J Neuroimmunol 76:81–90CrossRefGoogle Scholar
  21. Sweetman SC (2011) Martindale. The complete drug reference, 37th editions. The Pharmaceutical Press, LondonGoogle Scholar
  22. Visvesvara GS, Martinez AJ, Schuster FL, Leitch GJ, Wallace SV, Sawyer TK, Anderson M (1990) Leptomyxid ameba, a new agent of amebic meningoencephalitis in humans and animals. J Clin Microbiol 28:2750–2756Google Scholar
  23. Visvesvara GS, Schuster FL, Martinez AJ (1993) Balamuthia mandrillaris, N. G., N. Sp., agent of amebic meningoencephalitis in humans and other animals. J Eukaryot Microbiol 40:504–514CrossRefGoogle Scholar
  24. Visvesvara GS, Moura H, Schuster FL (2007) Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol Med Microbiol 50:1–26CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Huma Kalsoom
    • 1
  • Abdul Mannan Baig
    • 1
  • Naveed Ahmed Khan
    • 1
  • Ruqaiyyah Siddiqui
    • 1
  1. 1.Department of Biological and Biomedical SciencesAga Khan UniversityKarachiPakistan

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